Method of treating ulcers or hypersecretion

ABSTRACT

The invention concerns novel compounds of formula I 
     
         X--A--S--Y                                                 (I) 
    
     wherein X is a radical selected from imidazolyl, pyridyl, quinolyl, tetrahydropyridyl or piperidyl any of which may be substituted and Y is any of the above radicals or a pyridinium radical, A is alkylene of 1-6 carbon atoms. Most of the compounds are anti-ulcer agents but some have anti-hypertensive activity, e.g. where X is quinolyl. Methods of treating ulcers and anti-ulcer compositions are also described.

This is a division of application Ser. No. 217,925 filed Dec. 18, 1980now U.S. Pat. No. 4,343,805 which is a continuation of Ser. No. 98,421filed Nov. 29, 1979 now abandoned.

The invention relates to novel heterocyclic compounds which haveanti-ulcer, anti-secretory, and/or anti-hypertensive activity.

During the course of our search for novel anti-ulcer agents we havefound that certain novel compounds which have two particularheterocyclic rings (identified below) linked by an alkylene chaincontaining a sulphur atom, possess anti-ulcer and/or anti-secretoryactivity. Some of the compounds also have anti-hypertensive activity.Many of the compounds of our invention contain an imidazolyl ring. Somerelated nitroimidazoles have been disclosed recently in ArzneimittelForschung 1978, 351-366. These compounds have been investigated foractivity against various protozoa but so far as we are aware there hasbeen no report of any investigation for anti-ulcer activity. The relatedcompounds of our invention are distinguished from those of thispublication by the absence of a nitro group.

German Offenlegungsschrift No. 2,504,252 discloses a wide range ofheterocyclic compounds which are said to either inhibit or stimulategastric secretion. The compounds of our invention are distinguished fromthose of this German publication by having different combinations ofheterocyclic radicals.

According to the present invention, in one aspect, there is provided acompound of the formula I

    X--A--S--Y                                                 (I)

wherein X is a heterocyclic radical of the formula ##STR1## wherein R ishydrogen or lower alkyl, R¹ is hydrogen, lower alkyl, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkoxy, halogen, formyl, phenyl,phenylalkyl or acetal [CH(OR⁴)₂ where R⁴ is lower alkyl or two R⁴radicals are joined to form a lower alkylene chain], R² is hydrogen,lower alkyl, aryl, arylloweralkyl, halogen, nitro, loweralkoxy, hydroxy,amino, loweralkylamino, diloweralkylamino, trifluoromethyl or two R²radicals form a loweralkylene dioxygroup, n is 1, 2 or 3, m is 1 or 2,the dotted lines in formula V represent an optional double bond in oneof the indicated positions, A is a saturated or unsaturated alkyleneradical having from 1 to 6 carbon atoms, which may be substituted bylower alkyl of 1 to 6 carbon atoms; S is sulphur; Y is a heterocyclicradical of formula II to V as defined above, or of formula VII asdefined below: ##STR2## wherein R¹ and m are as defined above, R³ isloweralkyl, phenyl or aralkyl of 7 to 12 carbon atoms, and Z⁻ is ananion, and acid addition salts thereof, with the provisos that:

(1) when X and Y are both radicals of formula II at least onesubstituent R in X or Y is lower alkyl;

(2) when X is a radical of formula II and Y is a radical of formula IIIand both R¹ substituents are hydrogen then R is other than methyl,

(3) when X is a radical of formula III, then Y is a radical of formulaIII, IV, V or VII,

(4) when X is a 2-quinolyl radical and Y is a radical of formula II,III, IV, or V then the Y radical is linked to S at a position other thanthe 2-position,

(5) when X is a radical of formula II and Y is a radical of formula VIIthen A is CH₂,

(6) when more than one R¹ radical is present in the molecule then the R¹radicals may be the same of different, and

(7) when more than one R² radical is present in the molecule then the R²radicals may be the same or different.

Preferably Y is a radical of formula (VII), especially when X is aradical of formula II.

The radical A is preferably a saturated or unsaturated alkylene radicalof 1 to 6 carbon atoms which is unsubstituted. A may be methylene,ethylene, propylene, butylene, pentylene, or hexylene. Alternatively Amay be unsaturated containing at least one double bond eg --CH═CHCH₂ --.A radicals containing 1 to 4 carbon atoms are preferred, especially--CH₂ --.

The anion Z⁻ is preferably halide, namely fluoride, bromide, chloride oriodide or loweralkyl-, aryl- or aralkylsulphonate, eg methyl sulphonate(mesyl) or p-toluene sulphonate (tosyl).

In this specification when a group is substituted by alkyl, this ispreferably lower alkyl of 1 to 6 carbon atoms e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl and n-hexyl. Analkoxy substituent is preferably lower alkoxy in which the alkyl portionis as defined for a lower alkyl group. Whenever the term lower alkyl isused as part of another radical e.g. arylloweralkyl, the lower alkylportion has 1 to 6 carbon atoms.

The acid addition salts of compounds of formula I may be of an organicor inorganic acid e.g. hydrochloric, hydrobromic, phosphoric, sulphuric,nitric, citric, acetic, formic, fumaric, maleic, tartaric, embonic,methane sulphonic and p-toluene sulphonic acids.

The invention includes a pharmaceutical composition comprising acompound of formula I as defined above where proviso (2) does not applyor an acid addition salt thereof, and a pharmaceutically acceptablecarrier.

For the pharmaceutical carrier any suitable carrier known in the art canbe used to prepare the pharmaceutical compositions. In such acomposition, the carrier may be a solid, liquid, or mixture of a solidand a liquid. Solid form compositions include powders, tablets andcapsules. A solid carrier can be one or more substances which may alsoact as flavouring agents, lubricants, solubilisers suspending agents,binders, or tablet-disintegrating agents; it can also be anencapsulating material. In powders the carrier is a finely divided solidwhich is in admixture with the finely divided active ingredient. Intablets the active ingredient is mixed with a carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom 5 to 99, preferably 10-80% of the active ingredient. Suitable solidcarriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low melting wax and cocoa butter. Theterm "composition" is intended to include the formulation of an activeingredient with encapsulating material as carrier, to give a capsule inwhich the active ingredient (with or without other carriers) issurrounded by carriers, which is thus in association with it. Similarlycachets are included.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable carrier, such as sterilewater, sterile organic solvent or a mixture of both. The activeingredient can often be dissolved in a suitable organic solvent, forinstance aqueous propylene glycol containing from 10 to 75% of theglycol by weight is generally suitable. In other instances compositionscan be made by dispersing the finely-divided active ingredient inaqueous starch or sodium carboxymethyl cellulose solution, or in asuitable oil, for instance arachis oil.

Preferably the pharmaceutical composition is in unit dosage form, thecomposition is sub-divided in unit doses containing appropriatequantities of the active ingredient; the unit dosage form can be apackaged composition, the package containing specific quantities ofcompositions, for example packeted powders or vials or ampoules. Theunit dosage form can be a capsule, cachet or tablet itself, or it can bethe appropriate number of any of these in packaged form. The quantity ofactive ingredient in a unit dose of composition may be varied oradjusted from 10 to 500 mg or more e.g. 25 mg to 250 mg, according tothe particular need and the activity of the active ingredient. Theinvention also includes the compounds in the absence of carrier wherethe compounds are in unit dosage form.

The anti-ulcer compositions of the invention will be administered orallyin either liquid or solid composition form. These compositions mayinclude one or more antacid ingredients e.g. aluminium hydroxide,magnesium hydroxide or bismuth carbonate, aluminium glycinate, calciumcarbonate, magnesium trisilicate, sodium bicarbonate or the alumina geldescribed in British Specification No. 1,284,394.

Anti-ulcer activity was determined by the stress-induced erosion test ofSenay & Levine, Proc. Soc. Exp. Biol. Med., 124, 1221-3(1967) andanti-secretory activity by the test of H. Shay, D. Sun and H.Greenstein, Gastroentarology, 1954, 26, 903-13 as exemplified by Beattieet al J.Med. Chem., 20, 714 (1977). Compounds which possess one or boththese activities are considered to be anti-ulcer agents which can beused for the treatment of ulcers or hypersecretion in mammals. Nearlyall compounds of formula I which we have tested possess one or both ofthe above activities. However, some compounds show activity in tests foranti-hypertensive activity.

In another aspect the invention provides as an anti-ulcer agent acompound of formula I or an acid addition salt thereof as defined above,wherein proviso (2) does not apply, X is other than formula (IV), and ifX has formula III then A is at the 2-position of radical III.

The compounds may be prepared by methods known for analogous compounds.The invention includes methods of preparing the novel compounds of theinvention. For example a particularly useful method according to theinvention comprises reacting a compound of formula VIII

    X--A--Hal                                                  (VIII)

where X and A are as defined above and Hal is a halogen atom, with athiol compound of formula

    Y--SH

where Y is as defined above and provisos 1-5 apply or an alkali-metalderivative (where possible) of said thiol compound except when Y is VII.The thiol compound may be in the form of a tautomeric thione in suitablecases.

The invention includes a method of preparing novel compounds of formulaI wherein Y is a radical of formula VII and R³ is alkyl or aralkyl whichmethod comprises reacting a corresponding compound of formula I whereinY is a radical of formula III, with an alkylating or aralkylating agentcontaining the groups R³ and Z, eg with an alkyl or aralkyl halide or alower alkyl or aralkyl ester of an organic sulphonic acid such as aloweralkyl-, aralkyl- or aryl-sulphonic acid.

A compound I in which Z⁻ is one particular anion may be converted toanother in which Z⁻ is a different anion by anion exchange, eg chloridemay be exchanged for iodide by reaction of a chloride of formula I withsodium iodide in ethanol or other suitable solvent.

The following examples illustrate the invention:

EXAMPLE 1 1-Methyl-2(4-[5-methylimidazolyl]methylthio)pyridiniumchloride

1-Methyl-2-pyridothione (0.63 g, 0.005 mole) in hot ethanol (3 ml) wasadded to a refluxing solution of 4-chloromethyl-5-methylimidazole,hydrochloride (0.83 g, 0.005 mole) in ethanol (4 ml). The solution waswarmed on a steam bath for 5 minutes and allowed to crystallise. Thecrystals were removed by filtration, washed with ethanol and diethylether and dried to give the title compound as the hydrochloride salt(0.75 g) mp>260° C. (Found: C, 44.9; H, 5.35; N, 14.6. C₁₁ H₁₄ ClN₃ S,HCl requires C, 45.2; H, 5.2; N, 14.4%).

EXAMPLE 2 1-Methyl-2(2-pyridyl)methylthio)pyridinium chloride

1-methyl-2-pyridothione (1.1 g) was added to a solution of2-chloromethylpyridine, hydrochloride (1.28 g) in acetonitrile (10 ml).The solution was warmed 10 minutes on a steam bath and allowed tocrystallise. The crystals were removed by filtration, washed with etherand dried to give the title compound as the hydrochloride salt (2.0 g)mp 190° C. decomp. (Found: C, 49.4; H, 4.8; N, 9.4. C₁₂ H₁₃ N₂ SCl.HClrequires C, 49.8; H, 4.9; N, 9.7%).

EXAMPLE 3 1-Methyl-2(4-imidazolylmethylthio)pyridinium chloride

4-Chloromethylimidazole, hydrochloride (1.5 g) in ethanol (5 ml) wastreated with 1-methyl-2-pyridothione (1.25 g) in ethanol (5 ml) and themixture was heated on a steam bath for 5 minutes. The solution wasallowed to stand for 2 hours, scratched to induce crystallisation andether (20 ml) was added. The crystals were removed by filtration, washedwith ether and dried to give the title compound as the hydrochloridesalt (1.5 g) mp 228°-9° C. (Found: C, 43.1; H, 4.7; N, 15.1. C₁₀ H₁₂ N₃SCl, HCl requires C, 43.2; H, 4.7; N, 15.1%).

EXAMPLE 4 1-Methyl-2(4-[5-methylimidazolyl]methylthio)imidazole

A solution of 4-chloromethyl-5-methylimidazole, hydrochloride (1.67 g)in hot ethanol (12 ml) was filtered and treated with a solution of2-mercapto-1-methylimidazole (1.14 g) in hot ethanol (4 ml). The mixturewas heated on a steam bath for 2 hours and then allowed to cool. Theresulting solid was removed by filtration and washed with diethyl ether,followed by absolute ethanol and dried to give the title compound as thedihydrochloride monohydrate (1.4 g, 46%) mp 114°-7° C. (Found: C, 36.15;H, 5.5; N, 19.1%. C₉ H₁₂ N₄ S.2HCl.H₂ O requires: C, 36.1; H, 5.4; N,18.7%.

EXAMPLE 5 1-Methyl-2-(3-pyridylmethylthio)pyridinium chloride

A solution of 1-methyl-2-pyridothione (1.25 g) and3-chloromethylpyridine, hydrochloride (1.66 g) in ethanol (10 ml) washeated under reflux for 5 hours. The product was induced to crystalliseby scratching, removed by filtration, washed with ether and dried togive the title compound as the hydrochloride salt (2.2 g) mp 210°-2° C.(Found: C, 44.9; H, 5.2; N, 9.6. C₁₂ H₁₃ ClN₂ S.HCl requires C, 49.8; H,4.9; N, 9.7%).

EXAMPLE 6 2-(4-[5-Methylimidazolyl]methylthio)pyridine

A solution of 4-chloromethyl-5-methylimidazole, hydrochloride (1.67 g)in hot ethanol (20 ml) was filtered and treated with a solution of2-mercaptopyridine (1.1 g) in hot ethanol (10 ml). The mixture wasrefluxed for 3 hours and then cooled to room temperature. Diethyl etherwas added and the resulting solid was removed by filtration and dried togive the title compound as the dihydrochloride salt (1.78 g, 64%) mp203°-6° C. (Found: C, 42.8; H, 4.9; N, 15.45%. C₁₀ H₁₁ N₃ S.2HClrequires: C, 43.2; H, 4.7; H, 15.1%).

EXAMPLE 7 4-(4-[5-Methylimidazolyl]methylthio)pyridine

A solution of 4-chloromethyl-5-methylimidazole, hydrochloride (1.67 g)in hot ethanol (25 ml) was filtered and then added to a solution of4-mercaptopyridine (1.1 g) in hot ethanol (25 ml) under nitrogen. Themixture was refluxed under nitrogen for 21/2 hours. After cooling toroom temperature, a solid was precipitated out by the addition ofdiethyl ether. This was removed by filtration and dried to give thetitle compound as the dihydrochloride, hemihydrate (1 g, 35%) mp 240°-4°C. (Found: C, 41.55; H, 4.7; N, 14.6%. C₁₀ H₁₁ N₃ S.2HCl.1/2H₂ Orequires: C, 41.8; H, 4.9; N, 14.6%).

EXAMPLE 8 2-(4-Imidazolylmethylthio)pyridine

A solution of 4-chloromethylimidazole, hydrochloride (3.8 g) in hotethanol (25 ml) was treated with a solution of 2-mercaptopyridine (2.75g) in hot ethanol (25 ml). The mixture was heated under reflux for 1hour and then allowed to cool to room temperature. The resulting solidwas removed by filtration and dried to give the title compound as thedihydrochloride salt (5.2 g, 79%) mp 224°-6° C. (Found: C, 41.0; H, 4.3;N, 15.9. C₉ H₉ N₃ S.2HCl requires: C, 40.9; H, 4.2; N, 15.9%).

EXAMPLE 9 1-Methyl-2-([(4-pyridyl)methyl]thio)pyridinium chloride

1-Methyl-2-pyridothione (1.25 g) was added to a solution of 4-picolylchloride, hydrochloride (1.64 g) in hot isopropyl alcohol (20 ml). Themixture was heated under reflux for 2 hours and then allowed to cool toroom temperature. The resulting solid was removed by filtration anddried to give the title compound as the hydrochloride salt, threequarter hydrate (2.5 g; 83%) mp 178°-83° C. decomp. (Found: C, 47.75; H,5.4; N, 9.1%. C₁₂ H₁₃ ClN₂ S. HCl.3/4H₂ O requires: C, 47.6; H, 5.2; N,9.25%).

EXAMPLE 10 1-Methyl-2([(2-quinolyl)methyl]thio]pyridinium chloride

1-Methyl-2-pyridothione (1.25 g) was added to a solution of2-(chloromethyl)quinoline (2.14 g) in hot acetonitrile (35 ml). Themixture was heated under reflux for 3 hours. It was then allowed to coolto room temperature and was evaporated to dryness under reducedpressure. The residue was triturated with a small amount of hotacetonitrile. The resulting solid was removed by filtration and dried togive the title compound as the hydrochloride salt, monohydrate (1.8 g;50%) mp 142°-45° C. (Found: C, 53.9; H, 5.15; N, 8.0%. C₁₆ H₁₅ ClN₂S.HCl. H₂ O requires: C, 53.8; H, 5.1; N, 7.8%).

EXAMPLE 11 1-Methyl-2-[(2-piperidinoethyl)thio]pyridinium chloride

A solution of N-(2-chloroethyl)piperidine, hydrochloride (1.84 g) inethanol (20 ml) was treated with 1-methyl-2-pyridothione (1.25 g) andthe mixture was heated in a stainless steel bomb at 120° C. for 5 hours.It was then allowed to cool to room temperature and the solvent wasremoved by evaporation. The residue was triturated with ether and theresulting solid was removed by filtration and dried to give the titlecompound as the hydrochloride, one and one half hydrate (2.7 g; 80%) mp188°-90° C. (Found: C, 46.7; H, 7.1; N, 8.3%. C₁₃ H₂₁ ClN₂ S.HCl.11/2H₂O requires: C, 46.4; H, 7.5; N, 8.3%).

EXAMPLE 12

Using the method of example 2, 2-chloromethylpyridine is reacted withthe following pyridothiones to give the product indicated:

    ______________________________________                                        Pyrizothione       Product                                                    ______________________________________                                        (a)  3-hydroxymethyl-1-                                                                              1-phenyl-3-hydroxymethyl-                                   phenyl-2-pyridothione                                                                           2-((2-pyridyl)methylthio)                                                     pyridinium chloride                                    (b)  3-hydroxy-2-pyridothione                                                                        3-hydroxy-2-((2-pyridyl)                                                      methylthio)pyridine                                    (c)  1,4-dimethyl-2-pyridothione                                                                     2-((2-pyridyl)methylthio)-                                                    1,4-dimethylpyridinium                                                        chloride                                               (d)  3-(2-phenylethyl)-2-                                                                            3-(2-phenylethyl)-2-((2-                                    pyridothione pyridyl)methylthio)                                                                pyridine                                               (e)  3-phenyl-2-pyridothione                                                                         3-phenyl-2-((2-pyridyl)                                                       methylthio)pyridine                                    (f)  5-chloro-2-pyridothione                                                                         5-chloro-2-((2-pyridyl)                                                       methylthio)pyridine                                    (g)  3-formyl-1-methyl-2-                                                                            3-formyl-1-methyl-2-                                        pyridothione      (((2-pyridyl)methyl)thio)                                                     pyridinium chloride                                    (h)  3-hydroxymethyl-1-methyl-                                                                       3-hydroxymethyl-1-methyl-                                   2-pyridothione    2-(((2-pyridyl)methyl)thio)                                                   pyridinium chloride                                    (i)  3-diethoxymethyl-1-methyl-                                                                      3-diethoxymethyl-1-methyl-                                  2-pyridothione    2-(((2-pyridyl)methyl)thio)                                                   pyridinium chloride                                    ______________________________________                                    

EXAMPLE 13

Using the method of example 2, 1-methyl-2-pyridothione is reacted withthe following starting materials to give the product indicated:

    ______________________________________                                        Starting Material Product                                                     ______________________________________                                        (a)  2-chloromethyl-6-                                                                              2-((2-(6-methyl)pyridyl)                                     methylpyridine   methylthio)-1-methyl-                                                         pyridinium chloride                                     (b)  2-bromomethyl-6- 2-(2-(6-chloro)pyridyl)                                      chloropyridine   methylthio)-1-methylpyri-                                                     dinium bromide                                          (c)  2-chloromethyl-4-(-4-                                                                          2-((2-(4-(4-chlorophenyl))                                   chlorophenyl)pyridine                                                                          pyridyl)methylthio)-1-                                                        methylpyridinium chloride                               ______________________________________                                    

    ______________________________________                                        Pharmacological Test Results                                                            Stress-induced erosion                                                                        Anti-secretory                                      Compound  (Senay & Levine)                                                                              (Shay et al)                                        [Product of                                                                             Dose                Dose  % change                                  Example No.]                                                                            mg/kg   % inhibition                                                                              mg/kg in volume                                 ______________________________________                                        1         100     69          30    -65                                                                     10    -43                                       2         100     50          30    -31                                       3         100     67          30    -71                                                                     10    -43                                       4         100     83          30    -87                                                  30     58          10    -33                                       5         100     58          30    -55                                       6         100     68          30    --                                                   3      56                                                          7         100     87          30    -60                                       8         100     79          30    --                                                   30     70                                                          11        100     --          30    -35                                       ______________________________________                                    

ANTIHYPERTENSIVE ACTIVITY

Some compounds of the invention were tested for anti-hypertensiveactivity by the following procedures.

Procedure A

Systolic pressure of male spontaneously hypertensive rats is measured byan indirect technique using the Decker Caudal Plethylsmograph or otherappropriate sensor. Groups usually consist of 4 rats. Drugs are usuallyadministered orally. Pressures are usually read prior to drugadministration and at 1.5, 4 and 24 hours thereafter. This schedule maybe altered depending upon the behaviour of the drug.

Compounds of the following examples showed activity in this test at thedose stated. 75 mg/kg orally; Examples 3 and 5. 50 mg/kg orally;Examples 9 and 10.

The compound of Example 6 was inactive in this test at 75 mg/kg.

Procedure B

Female rats are rendered hypertensive by unilateral nephrectomy and thes.c. implantation of a pellet containing 30 mg of deoxycorticosteroneacetate. The drinking water is replaced by normal saline ad lib for thefirst four weeks following preparation. Blood pressures stabilise at ahypertensive level after 6 weeks. Systolic pressure is measuredindirectly before dosing with a test compound using an E and M pneumaticpulse transducer and a Devices MX2 recorder. Groups of 4 rats are dosedorally with suspensions or solutions of the test compound in 0.5%hydroxypropyl-methylcellulose 0.9% saline vehicle. Blood pressures arerecorded again at 2, 6 and 24 hours and the results, expressed as apercentage of the pre-dose values compared with those of a similar groupof rats receiving vehicle alone.

The compound of Example 4 was active in this test at 50 mg/kg orally.The compounds of examples 1 and 7 were inactive in this test at 50 mg/kgorally.

PHARMACEUTICAL COMPOSITIONS

The following examples illustrate the preparation of unit dosage form ofpharmaceutical compositions according to the invention.

EXAMPLE A

    ______________________________________                                        Antacid Tablet (chewable)                                                     ______________________________________                                        Saccharin               1.0     mg.                                           Hydrated alumina sucrose powder                                                                       750.0   mg.                                           N--Methyl-2(4-[5-methylimidazolyl]-                                                                   100.0   mg.                                           methylthio)pyridinium chloride                                                Mannitol B.P.           170.0   mg.                                           Maize starch B.P. dried 30.0    mg.                                           Talc. purified B.P.     28.0    mg.                                           Magnesium stearate B.P. 20.0    mg.                                           Peppermint oil B.P.     1.0     mg.                                                                   1100.0  mg                                            ______________________________________                                    

Antacid tablets of the above formulation are prepared by the followingprocedure. Triturate peppermint oil with talc (screen 40 mesh). Add thetriturate, and other ingredients to a blender and mix thoroughly. Slugthe powder to large hard slugs. Granulate the slugs through a 14 meshscreen. Compress the granules on a suitable compression machine to givetablets of the required size.

EXAMPLE B

    ______________________________________                                        Anti-ulcer tablet (without antacid)                                                                     mg/tablet                                           ______________________________________                                        N--Methyl-2(4-[5-methylimidazolyl]methylthio                                                            100    mg.                                          pyridinium chloride                                                           Celutab                   147.5  mg.                                          Mg. Stearate              2.5    mg.                                                                    250.0  mg.                                          ______________________________________                                    

The tablets are prepared by the following method. Blend the ingredientsin a suitable blender. Compress the blended ingredients on a suitablecompression machine to form tablets of the above composition. Celutab isa commercial product comprising 90-2% dextrose, 3-5% maltose, theremainder being higher glucose saccharides. The product is spraycrystallised.

EXAMPLES C TO F

Example A is repeated but replacingN-methyl-2(4-[5-methylimidazolyl]-methylthio)pyridinium chloride with100 mg of the products of Examples 3, 4, 5 and 7 respectively.

EXAMPLES G TO H

Example B is repeated but replacingN-methyl-2(4-[5-methylimidazolyl]-methylthio)pyridinium chloride with100 mg of the products of Examples 3, 4, 5 and 7 respectively.

The invention includes a method for the treatment of ulcers orhypersecretion in mammals which method comprises administering to saidmammal an effective amount of an anti-ulcer agent of formula I asdefined above. The amount of compound used will depend on the needs ofthe mammal being treated and the activity of the compound. Doses mayrange from 1 to 100 mg/kg.

We claim:
 1. A method of treating ulcers or hypersecretion in a mammalwhich comprises administering to said mammal an effective anti-ulceramount of a compound of formula I ##STR3## wherein Y is ##STR4## whereinR is hydrogen or lower alkyl, R¹ is hydrogen, lower alkyl, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkoxy, halogen, formyl, phenyl,phenylalkyl or CH(OR⁴)₂ where R⁴ is lower alkyl or two R⁴ radicals arejoined to form a lower alkylene chain, m is 1 or 2, the dotted lines informula V represent an optional double bond in one of the indicatedpositions, the nitrogen atom carrying a positive charge when a doublebond is in the position adjacent thereto, A is an alkylene radicalhaving from 1 to 6 carbon atoms, which may be substituted by lower alkylof 1 to 6 carbon atoms, S is sulphur, R³ is loweralkyl, phenyl oraralkyl of 7 to 12 carbon atoms, Z⁻ is an anion, or a pharmaceuticallyacceptable acid addition salt thereof, with the proviso that when morethan one R¹ radical is present in the molecule then the R¹ radicals maybe the same or different.
 2. A method as claimed in claim 1 wherein thecompound of formula I is 1-methyl-2-[piperidinoethyl)thio]pyridiniumchloride or a pharmaceutically acceptable acid addition salt thereof.